Project Summary Inhibiting the growth hormone (GH)-insulin-like growth factor-1 (IGF-1) signaling pathway by dietary or genetic manipulation extends lifespan in a range of species, including possibly humans. However, achieving this effect pharmacologically has proven difficult. FGF21 is a hormone that is released from the liver in response to fasting and elicits diverse aspects of the adaptive starvation response. Among its metabolic actions in mice, FGF21 causes GH resistance and consequently a marked reduction in circulating IGF-1 concentrations. Remarkably, transgenic mice overexpressing FGF21 from birth live 30-40% longer than wild-type mice. In the studies proposed in this application, we will test whether FGF21 causes a corresponding increase in the healthspan of mice as assessed by measuring strength, immune system and cognitive function. We will further determine whether initiating exposure to FGF21 in adulthood also extends lifespan and healthspan. Lastly, we will test whether FGF21 suppresses the GH-IGF-1 pathway by inducing suppressor of cytokine signaling protein 2, which has well established anti-GH effects. Since several pharmaceutical companies already have FGF21 in clinical trials for treating obesity and type 2 diabetes, FGF21 administration may be a viable approach for extending healthspan and lifespan in humans.